Hepatic Metabolic Control of Meal Size and Number

描述(申请人提供)：由于很难清楚地确定能量代谢在控制正常摄食中的作用，本申请提出了对大鼠肝脏代谢控制正常自然摄食的机制的行为、生理和遗传学研究。我们的假设是，肝脏摄取食物的代谢结果会产生负反馈信号，这些信号通过迷走神经传入神经元到达大脑，并在大脑中起作用，终止摄取，限制食物的摄入量(即产生饱足感)。此外，我们假设相关的代谢事件是肝细胞葡萄糖和脂肪酸利用的生化整合的结果，并且它们受到肝糖原含量的调节。提出了7个具体目标来确定：(1)肝细胞ATP能量状态的改变是否足以影响自发进食量或进食量；(2)肝细胞对碳水化合物或中链脂肪酸的利用是否足以减少自发进食量或进食量；(2)肝细胞对碳水化合物或中链脂肪酸的利用变化是否足以影响自发进食量或进食量；(3)肝糖原含量是否调节肝细胞对自发进食的代谢控制；(4)迷走神经在肝细胞对自发进食的代谢控制中的作用；(5)脑干和下丘脑的哪些区域被自发进食的肝细胞代谢控制所激活；(6)在自发进食的肝细胞代谢控制中是否存在雌二醇敏感的性别差异；以及(7)在转基因大鼠中，肝细胞对进食大小的控制是否存在表型差异，这些转基因大鼠的肝细胞代谢途径的关键酶可诱导地过表达(敲入)影响进食大小的关键酶。由于进食障碍是神经性厌食症、神经性贪食症和肥胖症的主要特征，而且在NIDDM等综合征中，食物摄取的代谢控制可能会受到干扰，因此拟议的研究应该贡献新的基本生理学知识，可能有助于促进对人类健康问题的理解和治疗。该项目的工作将作为一个联合体进行，以利用瑞士苏黎世瑞士联邦理工学院的PI和纽约州怀特普莱恩斯康奈尔大学威尔医学院的共同PI的独特专业知识。

DESCRIPTION (provided by applicant): Because it has proven difficult to establish clearly the role of energy metabolism in the control of normal feeding, this application proposes behavioral, physiological, and genetic studies of the mechanisms by which hepatic metabolism controls normal spontaneous feeding in rats. Our hypothesis is that hepatic metabolic consequences of food ingestion generate negative feedback signals that reach the brain via vagal afferent neurons and act in the brain to terminate ingestion and limit meal size (i.e., produce satiation). Furthermore, we hypothesize that the relevant metabolic events result from the biochemical integration of hepatocellular glucose and fatty acid utilization and that they are modulated by liver glycogen content. Seven specific aims are proposed to determine: (1) whether changes in hepatocellular ATP energy status are sufficient to affect spontaneous meal size or meal number; whether hepatocellular utilization of carbohydrate or medium-chain fatty acids is sufficient to reduce spontaneous meal size or meal number; (2) whether changes in hepatocellular utilization of carbohydrate or medium-chain fatty acids are sufficient to affect spontaneous meal size or meal number; (3) whether hepatic glycogen content modulates the hepatocellular metabolic control of spontaneous feeding; (4) the role of the vagus nerve in hepatocellular metabolic control of spontaneous feeding; (5) which areas of the brainstem and hypothalamus are activated by manipulations of hepatocellular metabolic controls of spontaneous feeding; (6) whether there are estradiol-sensitive sex differences in hepatocellular metabolic controls of spontaneous feeding; and (7) if there are phenotypic differences in the hepatocellular control of meal size in transgenic rats with inducible over-expressions (knock in) of key enzymes of the putative hepatocellular metabolic pathways affecting meal size. Because disordered eating is a central feature anorexia nervosa, bulimia nervosa, and obesity and because metabolic controls of food intake may be disturbed in syndromes such as NIDDM, the proposed studies should contribute new basic physiological knowledge that may facilitate advances in understanding and treating human health problems. Work on this project will be done as a consortium to capitalize on the unique expertise of the PI at Swiss Federal Institute for Technology, Zurich, Switzerland, and the co-PI, at Weill Medical College of Cornell University, White Plains, NY.